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In a poorly understood yet recurring phenomenon, communities occupying diverse settings within a region may undertake large-scale migrations that cannot be easily attributed to single variables such as climate change. As a result, the study of these movements has increasingly focused on the distinct histories of localities to address how they may have articulated as large-scale abandonments. We adopt this micro-history perspective on the fourteenth to fifteenth century depopulation of a large portion of the North American Midwest and Southeast, popularly referred to as the Vacant Quarter. Our research on the Middle Cumberland drainage within the Vacant Quarter suggests that a significant exodus began slowly ca. 1300 CE, then accelerated extremely rapidly in the first half of the fifteenth century CE. This genesis of this trajectory seems to be related to a pattern of severe droughts, but it was brought to a close by social and demographic challenges such as endemic conflict and adverse health conditions.